Noise-induced hearing loss (NIHL) is a significant clinical, social, and economic issue;resolving this important health issue is central to the mission of the NIDCD. Our long-term strategic program of "bedside to laboratory bench to bedside" directly leads to the current proposal to translate an intervention from "bench to bedside". Ten years of NIDCD funding for studies in animals have allowed us to identify mechanisms contributing to NIHL, including direct mechanical trauma, free radicals formed in association with metabolic stress, and reduced blood flow. We have now identified a combination of micronutrients (antioxidants and other agents) as highly effective in preventing NIHL in animals. This treatment significantly attenuates sensory cell death in the inner ear and corresponding threshold deficits. The proposed studies, conducted by an international team including basic scientists, otolaryngologists, and audiologists, will demonstrate efficacy of this therapeutic intervention in humans during carefully-controlled clinical trials with real-world noise insults. Specific Aim 1 will verify therapeutic efficacy with real-world noise insults that induce temporary threshold shifts;these studies will focus on loud music under laboratory conditions, and military urban warfare training exercises. Specific Aim 2 will verify therapeutic efficacy in humans exposed to occupational noise on a daily basis, including aircraft noise experienced by pilots and ground crew, and machine noise experienced by cutlery workers. Availability of an effective treatment will reduce development of hearing loss in at-risk human populations, thereby improving quality of life for millions and decreasing healthcare costs for individuals, businesses, and government agencies. Funds are therefore requested to initiate a series of Phase II clinical trials to demonstrate for the first time the effectiveness of this intervention in man. This program is intended to be the first translational research step to eliminate NIHL in the 21st century. Noise-induced hearing loss is an important medical, social, and economic issue. We have identified a treatment that reduces inner ear cell death and hearing loss in animals. These studies will demonstrate efficacy of this treatment in humans. This prevention will improve quality of life for the millions exposed to noise, and decrease healthcare costs for individuals, businesses, and government agencies.